2-Amino-9-aryl-3-cyano-4-methyl-7-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]thieno[2,3- b]pyridine derivatives as selective progesterone receptor agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 17; pp. 4916 - 4919
• Main Authors: Wang, Yonghui, Duraiswami, Chaya, Madauss, Kevin P., Tran, Thuy B., Williams, Shawn P., Deng, Su-Jun, Graybill, Todd L., Hammond, Marlys, Jones, David G., Grygielko, Eugene T., Bray, Jeffrey D., Thompson, Scott K.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.09.2009; Elsevier
• Subjects: Agonists; Animals; Binding Sites; Biological and medical sciences; Computer Simulation; Crystallography, X-Ray; Endometriosis; Hormones. Endocrine system; Humans; Medical sciences; Microsomes, Liver - metabolism; Molecular Conformation; Nuclear receptor; Pharmacology. Drug treatments; Progesterone; Progesterone receptor; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyridones - chemical synthesis; Pyridones - chemistry; Pyridones - pharmacology; Rats; Receptors, Progesterone - agonists; Receptors, Progesterone - metabolism; Selective agonists; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; Agonists; Selective agonists; Endometriosis; Nuclear receptor; Progesterone; Progesterone receptor; Sulfur nitrogen heterocycle; Agonist; Nitrile; Benzene derivatives; Lactam; Selectivity; Tricyclic compound; In vitro; Structure activity relation; Chlorine Organic compounds; Affinity; Chemical synthesis; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.07.100

A novel series of 2-amino-9-aryl-3-cyano-4-methyl-7-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]thieno[2,3- b]pyridine derivatives was identified as selective PR agonists. Initial SAR exploration, X-ray crystal structure of 9 bound to PR-LBD, and some preliminary developability data are described. High throughput screening of the corporate compound collection led to the identification of a novel series of 2-amino-9-aryl-3-cyano-4-methyl-7-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]thieno[2,3- b]pyridine derivatives as selective PR agonists. Initial SAR exploration leading to potent and selective agonists 9 and 11, X-ray crystal structure of 9 bound to PR-LBD and preliminary developability data are described.